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The Mechanism Of Sortase Catalyzed Cell Wall Anchoring Of Surface Proteins During Gram Positive Bacterial Infections
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Book Synopsis The Mechanism of Sortase Catalyzed Cell Wall Anchoring of Surface Proteins During Gram-positive Bacterial Infections by : Sarkis Krikor Mazmanian
Download or read book The Mechanism of Sortase Catalyzed Cell Wall Anchoring of Surface Proteins During Gram-positive Bacterial Infections written by Sarkis Krikor Mazmanian and published by . This book was released on 2002 with total page 318 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Sortase Enzyme Mediated Surface Protein Display in Gram-positive Bacteria by : Albert Hay Wah Chan
Download or read book Sortase Enzyme Mediated Surface Protein Display in Gram-positive Bacteria written by Albert Hay Wah Chan and published by . This book was released on 2014 with total page 173 pages. Available in PDF, EPUB and Kindle. Book excerpt: Staphylococcus aureus is a leading cause of hospital-acquired infections in the United States. The rapid emergence of multidrug-resistant strains has created an urgent need for new antibiotics. S. aureus and other Gram-positive pathogens use sortase enzymes to display surface virulence factors to promote infections. Compounds that inhibit sortase might therefore function as potent anti-infective agents. This dissertation focuses on the discovery of sortase A (SrtA) inhibitors, as well as more fundamental studies of the mechanism of catalysis. Both structural (NMR) and in silico approaches were used for inhibitor development, which resulted in the discovery of a very potent pyridazinone class compound that effectively inhibits S. aureus SrtA at nanomolar concentrations. This compound and its related derivatives also inhibit Bacillus anthracis SrtA, but they are not toxic to human cells. Therefore, they are promising leads for further development into a therapeutic. To gain insights into the sortase catalytic mechanism, I also determined the 3D structure of the B. anthracis SrtA bound to a substrate analog using NMR methods. The structure reveals a novel N-terminal extension that regulates substrate entry, and a substrate-induced disorder to order transition of one of the active site loops. Ultimately, this new structural information may be useful in guiding the design of pan-sortase inhibitors that can be used to treat a broad spectrum of bacterial infections.
Book Synopsis Anchoring of Surface Proteins to the Cell Wall of Gram-positive Bacteria by : William Wiley Navarre
Download or read book Anchoring of Surface Proteins to the Cell Wall of Gram-positive Bacteria written by William Wiley Navarre and published by . This book was released on 1999 with total page 364 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis Protein and Sugar Export and Assembly in Gram-positive Bacteria by : Fabio Bagnoli
Download or read book Protein and Sugar Export and Assembly in Gram-positive Bacteria written by Fabio Bagnoli and published by Springer. This book was released on 2017-05-02 with total page 342 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book focuses on the envelope of Gram-positive bacteria including its composition, the latest discoveries in the mechanisms behind its assembly, and its role in pathogenesis. Furthermore, new applications in biotechnology and vaccine development involving these bacteria are discussed in detail. This concise volume consists of eleven chapters by prominent experts in the field, which review the latest findings and current state of knowledge on a range of diverse yet interlinked aspects. This book is written for all researchers, clinicians and technicians engaged in basic or applied science projects on Gram-positive bacteria.
Book Synopsis Cell Surface Proteins of Gram-positive Pathogenic Bacteria by : Magnus Hook
Download or read book Cell Surface Proteins of Gram-positive Pathogenic Bacteria written by Magnus Hook and published by Frontiers Media SA. This book was released on 2021-07-14 with total page 170 pages. Available in PDF, EPUB and Kindle. Book excerpt:
Book Synopsis The Kinetic and Structural Investigation of Pilus Assembly and the Development of Sortase Inhibitors for Gram-Positive Bacteria by : Christopher Kenji Sue
Download or read book The Kinetic and Structural Investigation of Pilus Assembly and the Development of Sortase Inhibitors for Gram-Positive Bacteria written by Christopher Kenji Sue and published by . This book was released on 2022 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Pathogenic multidrug resistant bacteria cause a range of serious infections in humans. These bacteria have developed mechanisms to counteract the lethal effects of currently used antibiotics, creating a need for novel therapeutics. Gram-positive bacteria display a wide assortment of cell surface proteins that are important for bacterial survival and host-pathogen interactions. These key surface structures included pili, proteinaceous fibers that assist in microbial survival by mediating adhesion to host tissues and aid in the formation of biofilm. A large number of gram-positive bacterial species assemble pili and append surface proteins to the cell wall using sortase cysteine transpeptidase enzymes. These enzymes link the components of the pilus together via covalent lysine isopeptide bonds which confer enormous tensile strength. This dissertation describes my investigation of the assembly mechanism of the archetypal SpaA-pilus from Corynebacterium diphtheriae. It also describes my contributions to develop small molecule sortase inhibitors that could function as anti-infective agents and my work towards exploiting the activity of sortase enzymes as a protein engineering tool. This thesis focuses on sortase enzymes and can be divided into two major sections: studies to determine how sortases construct pili (Chapters 2-4) and work designed to discover a small molecule inhibitor for the Staphylococcus aureus Sortase A enzyme (Chapter 5). All of the studies have been published in peer reviewed papers, with the exception of work detailed in Chapter 4. Chapter 2 describes the NMR solution structure of the lysine isopeptide bond interface that connects the pilin components of the pilus. This structural information combined with biophysical and cellular analyses led to the formulation of the "latch" mechanism of pilus assembly. Chapter 3 describes an enzyme kinetic study of the sortase enzyme from C. diphtheriae (CdSrtA) which catalyzes the formation of lysine isopeptide bonds between components of the SpaA pilus. In this study, the rate-limiting step of catalysis was determined and variants of CdSrtA with improved activity were discovered. Chapter 4 describes research that employed biochemical and structural approaches to investigate how the incorporation of the SpaB pilin subunit terminates pilus assembly. Key differences were observed between the reaction that terminates assembly and the process of polymerization that builds the shaft of the pilus. Chapter 5 describes efforts to discover a small molecule inhibitor of the Staphylococcus aureus Sortase A enzyme that has the potential to be a therapeutically useful anti-infective agent. The first half of Chapter 5 describes the work done to improve the activity of previously discovered pyridazinone-based molecules using computational and synthetic chemistry methods. The second half describes the implementation of a novel cell-based screen to identify sortase inhibitors. This work leveraged the unique sortase-dependent growth phenotype of Actinomyces oris to screen for sortase inhibitors. Over 200,000 small molecules were screened for their ability to impair A.oris's growth, which led to the identification of three molecular scaffolds that inhibit sortase activity in vitro. In totality, my thesis research has shed light on how sortase enzymes assemble pili in gram-positive bacteria, led to improved variants of CdSrtA sortase that can be used in protein engineering, and helped identify new small molecule sortase inhibitors with potential therapeutic applications.
Book Synopsis Gram-positive Pathogens by : Vincent A. Fischetti
Download or read book Gram-positive Pathogens written by Vincent A. Fischetti and published by . This book was released on 2000 with total page 760 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book is the only single volume to deal with all aspects of gram–positive pathogens. It addresses the mechanisms of gram–positive bacterial pathogenicity, including the current knowledge on gram–positive structure and mechanisms of antibiotic resistance. Emphasizing streptococci, staphylococci, listeria, and spore–forming pathogens, Gram–Positive Pathogens includes chapters written by many of the leading researchers in these areas. The chapters systematically dissect these organisms biologically, genetically, and immunologically in an attempt to understand the strategies used by these bacteria to cause human disease.
Download or read book CRISPR-Cas Enzymes written by and published by Academic Press. This book was released on 2019-01-25 with total page 454 pages. Available in PDF, EPUB and Kindle. Book excerpt: CRISPR-Cas Enzymes, Volume 616, the latest release in the Methods in Enzymology series, continues the legacy of this premier serial with quality chapters authored by leaders in the field. Topics covered in this release include CRISPR bioinformatics, A method for one-step assembly of Class 2 CRISPR arrays, Biochemical reconstitution and structural analysis of ribonucleoprotein complexes in Type I-E CRISPR-Cas systems, Mechanistic dissection of the CRISPR interference pathway in Type I-E CRISPR-Cas system, Site-specific fluorescent labeling of individual proteins within CRISPR complexes, Fluorescence-based methods for measuring target interference by CRISPR-Cas systems, Native State Structural Characterization of CRISRP Associated Complexes using Mass Spectrometry, and more. - Provides the authority and expertise of leading contributors from an international board of authors - Presents the latest release in the Methods in Enzymology series - Updated release includes the latest information on the CRISPR-Cas Enzymes
Book Synopsis Mechanism and Function of Membrane Homeostasis of Sortase Modulated by an Evolutionarily Conserved Protein Involved in Pilus Assembly in Actinobacteria by : Nicholas Anthony Ramirez
Download or read book Mechanism and Function of Membrane Homeostasis of Sortase Modulated by an Evolutionarily Conserved Protein Involved in Pilus Assembly in Actinobacteria written by Nicholas Anthony Ramirez and published by . This book was released on 2022 with total page 99 pages. Available in PDF, EPUB and Kindle. Book excerpt: Bacteria utilize proteins at their surface for a multitude of processes including adhesion, biofilm formation, motility, and virulence. Thus, understanding the biogenesis and surface display of these factors is instrumental in our understanding of bacterial pathogenesis and virulence mechanisms. Within this dissertation we describe the identification and characterization of a newly identified peptide which is functionally conserved amongst Actinobacteria and serves to modulate anchoring of proteins to the cell wall through modulation of membrane homeostasis of the housekeeping sortase. In the oral cavity associated bacterial species, Actinomyces oris, we identified a small peptide consisting of 52 amino acids which is encoded directly downstream of the gene encoding the housekeeping sortase SrtA. Henceforth we refer to this peptide as SafA for Sortase Associated Factor A. Firstly, through bioinformatic analysis we found that nearly all Actinobacteria encode a SafA homolog immediately downstream of their respective housekeeping sortase genes, with the exception of Bifidobacterium dentium in which the genome does not contain a separate SafA reading frame, but rather the C-terminus of the housekeeping sortase harbors a domain homologous to SafA in A. oris. In A. oris we found that deletion of safA results in phenotypes consistent with deletion of the housekeeping sortase itself, which include the formation of abnormally long pili as detected by electron microscopy and the failure of A. oris to interact with another oral bacterial species Streptococcus oralis. Cellular fractionation and immunoblotting revealed that in the absence of SafA, SrtA is cleaved and released into the extracellular milieu. While software predictions did not identify a signal peptide sequence in SrtA, manual amino acid sequence, sequence analysis did in fact reveal that SrtA contains a tripartite domain consistent with a type I signal peptide sequence and a predicted cleavage site between A56 and S57. Edman degradation amino acid sequencing confirmed this cleavage site and mutational analysis revealed that the signal peptidase LepB2 is responsible for this observed cleavage of SrtA. To elucidate how SafA protects SrtA from cleavage we utilized a Bacterial Adenylate Cyclase Two-Hybrid system which demonstrated that SafA and SrtA directly interact. Furthermore, we identified a three amino acid domain in SafA consisting of FPW residues which is essential for mediating this interaction. Finally, we found that ectopic expression of SafA from A. oris, Corynebacterium diphtheriae, and Corynebacterium matruchotii rescued the aforementioned functional defects of the safA mutant of A. oris, thus supporting the conclusion that SafA is both functionally and evolutionarily conserved. The findings described herein demonstrate a new paradigm for the modulation surface protein display in Actinobacteria. The conservation of SafA across Actinobacteria coupled with the essential role for sortases in mediating anchoring of pili and key virulence factors provides a unique target and opportunity to inhibit the virulence of Actinobacteria species.
Book Synopsis Biogenesis of Fatty Acids, Lipids and Membranes by : Otto Geiger
Download or read book Biogenesis of Fatty Acids, Lipids and Membranes written by Otto Geiger and published by Springer. This book was released on 2019-01-29 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Concise chapters, written by experts in the field, cover a wide spectrum of topics on lipid and membrane formation in microbes (Archaea, Bacteria, eukaryotic microbes).All cells are delimited by a lipid membrane, which provides a crucial boundary in any known form of life. Readers will discover significant chapters on microbial lipid-carrying biomolecules and lipid/membrane-associated structures and processes.
Book Synopsis Structural and Mechanistic Enzymology by :
Download or read book Structural and Mechanistic Enzymology written by and published by Academic Press. This book was released on 2017-07-17 with total page 277 pages. Available in PDF, EPUB and Kindle. Book excerpt: Structural and Mechanistic Enzymology, Volume 109, the latest release in the Advances in Protein Chemistry and Structural Biology series, is an essential resource for protein chemists. Chapters in this new volume include Collagenolytic Matrix Metalloproteinase Structure–Function Relationships: Insights from Molecular Dynamics Studies, Computational Glycobiology: Mechanistic Studies of Carbohydrate-Active Enzymes and Implication for Inhibitor Design, Computational Biochemistry-Enzyme Mechanisms Explored, and A Paradigm for C-H Bond Cleavage: Structural and Functional Aspects of Transition State Stabilization by Mandelate Racemase. This series presents new information on protocols and analysis of proteins, with each volume guest edited by leading experts in a broad range of protein-related topics. This volume presents state-of-the-art contributions, providing insights into the relationship between enzyme structure, catalysis, and function. - Provides cutting-edge developments in protein chemistry and structural biology - Features new information about protocols and analysis of proteins - Contains chapters written by authorities in their respective fields - Targeted to a wide audience of researchers, specialists and students
Book Synopsis Structural and Biochemical Investigation of Gram-Positive Bacterial Surface Display Machinery by : Brendan Rayhan Amer
Download or read book Structural and Biochemical Investigation of Gram-Positive Bacterial Surface Display Machinery written by Brendan Rayhan Amer and published by . This book was released on 2017 with total page 164 pages. Available in PDF, EPUB and Kindle. Book excerpt: Many species of pathogenic Gram-positive bacteria have become resistant to commonly used antibiotics, creating a pressing need for the development of novel antimicrobial therapies. These pathogenic bacteria are surrounded by a complex peptidoglycan cell wall that is decorated with a range of macromolecules such as surface proteins, protein-based oligomeric pili, and surface glycopolymers. These structures enable the microbe to effectively interact with their environment, and in pathogenetic bacteria are frequently virulence factors that are involved in: immune system modulation, bacterial adhesion, nutrient acquisition, and spore formation. Two distinct enzyme superfamilies are primarily responsible for covalently attaching macromolecules to the Gram-positive cell wall: sortase enzymes that attach proteins and assemble pili, and LytR-Psr-CpsA (LCP) enzymes that attach glycopolymers. This dissertation presents my efforts to discover a sortase inhibitor, structural and mechanistic investigations of both sortase and LCP enzymes, and the development of a new sortase mediated ligation technology. I describe our efforts to find inhibitors against the S. aureus sortase transpeptidase. We utilized both experimental and computational methods to discover potent inhibitor scaffolds. This led to structure-activity studies that not only improved inhibitor potency, but also yielded molecules that can inhibit bacterial protein display in vivo, and appear to be non-toxic to human cells. Sortase enzymes have also proven to be valuable biotechnological conjugation tools. I describe the development of a novel sortase-mediated ligation tool. We demonstrate a 15-fold rate enhancement for existing sortase mediated ligation strategies. Additionally, I discuss studies on sortase pilus assembly and display. To gain insight into the molecular mechanism of sortase pilus assembly, we reconstituted an archetypal Gram-positive pilus assembly process in vitro. This has allowed us to generate molecular models of various intermediates of pilus assembly and define the molecular determinants of this assembly process. We have identified novel features on both the sortase and pilin precursor proteins that are essential for pilus covalent isopeptide assembly. In the concluding chapter of this dissertation, structural work characterizing the unique LCP enzyme that mediates surface protein glycosylation is presented. Work on this project reveals that LCP enzymes use a conserved phosphotransferase mechanism to attach glycopolymers to surface displayed proteins, and this may be a mechanism for actinobacteria wall teichoic acid display, a key macromolecule in the bacterial cell envelope. Combined, this work serves to further define the mechanism of Gram-positive bacterial macromolecular surface display, improved sortase-mediated bioconjugation strategies, and steps towards novel anti-infective sortase inhibitors.
Book Synopsis Bacterial Cell Wall by : J.-M. Ghuysen
Download or read book Bacterial Cell Wall written by J.-M. Ghuysen and published by Elsevier. This book was released on 1994-02-09 with total page 607 pages. Available in PDF, EPUB and Kindle. Book excerpt: Studies of the bacterial cell wall emerged as a new field of research in the early 1950s, and has flourished in a multitude of directions. This excellent book provides an integrated collection of contributions forming a fundamental reference for researchers and of general use to teachers, advanced students in the life sciences, and all scientists in bacterial cell wall research. Chapters include topics such as: Peptidoglycan, an essential constituent of bacterial endospores; Teichoic and teichuronic acids, lipoteichoic acids, lipoglycans, neural complex polysaccharides and several specialized proteins are frequently unique wall-associated components of Gram-positive bacteria; Bacterial cells evolving signal transduction pathways; Underlying mechanisms of bacterial resistance to antibiotics.
Book Synopsis Molecular Assembly in Natural and Engineered Systems by :
Download or read book Molecular Assembly in Natural and Engineered Systems written by and published by Academic Press. This book was released on 2011-10-12 with total page 427 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume explores some of the most exciting recent advances in basic research on molecular assembly in natural and engineered systems and how this knowledge is leading to advances in the various fields. - This series provides a forum for discussion of new discoveries, approaches, and idea - Contributions from leading scholars and industry experts - Reference guide for researchers involved in molecular biology and related fields
Book Synopsis Lipid Modification of Proteins by : N. M. Hooper
Download or read book Lipid Modification of Proteins written by N. M. Hooper and published by Oxford University Press, USA. This book was released on 1992 with total page 318 pages. Available in PDF, EPUB and Kindle. Book excerpt: Lipid Modification of Proteins: A Practical Approach is a unique guide to the latest methods is use, written by the acknowledged experts in the field. Detailed protocols are provided for all the key techniques, and the relevant background material is included. This book is an essential manual for a wide range of scientists studying the modification of protein by lipids, including membrane and protein biochemists, cell biologists, immunologists, bacteriologists, parasitologists, and virologists.
Book Synopsis The Microbiology of Central Nervous System Infections by :
Download or read book The Microbiology of Central Nervous System Infections written by and published by Academic Press. This book was released on 2018-02-17 with total page 348 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Microbiology of Central Nervous System Infections, Volume 3, discusses modern approaches to the diagnosis, treatment and prophylaxis of central nervous system (CNS) infections. This new release is divided into five sections that cover treatment strategies, imaging, molecular diagnosis, management of CNS infections with metal nanoparticles, and prophylaxis of CNS infections, including bacterial, viral and fungal infections. The last section contains a chapter on transmissible spongiform encephalopathies and modern trends in its diagnosis and treatment. University teachers, medical practitioners, graduate and postgraduate students, researchers in microbiology, and those in the pharmaceutical and laboratory diagnostic industries will find the book very important. - Encompasses a broad range of central nervous system infections, including questions of etiology, pathogenesis, diagnosis, prognosis, treatment and prophylaxis - Written by highly professional and eminent surgeons, microbiologists and infectious disease specialists - Includes scientific understanding and practical guidelines, making it interesting for both research scientists and practitioners
Book Synopsis The Perfect Slime by : Hans-Curt Flemming
Download or read book The Perfect Slime written by Hans-Curt Flemming and published by IWA Publishing. This book was released on 2016-09-15 with total page 336 pages. Available in PDF, EPUB and Kindle. Book excerpt: The Perfect Slime presents the latest state of knowledge and all aspects of the Extracellular Polymeric Substances, (EPS) matrix – from the ecological and health to the antifouling perspectives. The book brings together all the current material in order to expand our understanding of the functions, properties and characteristics of the matrix as well as the possibilities to strengthen or weaken it. The EPS matrix represents the immediate environment in which biofilm organisms live. From their point of view, this matrix has paramount advantages. It allows them to stay together for extended periods and form synergistic microconsortia, it retains extracellular enzymes and turns the matrix into an external digestion system and it is a universal recycling yard, it protects them against desiccation, it allows for intense communication and represents a huge genetic archive. They can remodel their matrix, break free and eventually, they can use it as a nutrient source. The EPS matrix can be considered as one of the emergent properties of biofilms and are a major reason for the success of this form of life. Nevertheless, they have been termed the “black matter of biofilms” for good reasons. First of all: the isolation methods define the results. In most cases, only water soluble EPS components are investigated; insoluble ones such as cellulose or amyloids are much less included. In particular in environmental biofilms with many species, it is difficult to impossible isolate, separate the various EPS molecules they are encased in and to define which species produced which EPS. The regulation and the factors which trigger or inhibit EPS production are still very poorly understood. Furthermore: bacteria are not the only microorganisms to produce EPS. Archaea, Fungi and algae can also form EPS. This book investigates the questions, What is their composition, function, dynamics and regulation? What do they all have in common?
